PROJECT SUMMARY/ABSTRACT We and other groups are developing an electronic retinal prosthesis to provide sight to individuals who are blind due to age-related macular degeneration (AMD) or retinitis pigmentosa (RP). The common phenotype of these retinal dystrophies is photoreceptor degeneration. Retinal ganglion cells (RGCs), the output neurons of the retina, remain intact and can still transmit information to the visual centers of the brain. Consequently, an implantable retinal prosthesis can stimulate the remaining viable retina, circumventing the degenerated photoreceptors. Several clinical trials using retinal implants are currently underway in the United States and Germany. These trials are presently being conducted in subjects with advanced RP, with little or no light perception. A major concern from the findings of the human trials is that relatively high levels of electric current are needed to evoke visual percepts in blind subjects. This is in contrast to the amount of current needed to elicit a visual percept in normal-sighted individuals. The long-term objectives of the present study are to better understand why more current is required to elicit visual percepts in blind individuals than in normal-sighted individuals and to determine strategies for lowering stimulation thresholds in diseased retinas. In this proposal, we will determine the relationship between stimulation thresholds of RGCs and the extent of retinal degeneration in an animal model of RP. The extent of retinal degeneration will be assessed by measuring components of the electroretinogram (ERG) and the thickness of the outer nuclear layer (ONL), which contains photoreceptors. We will also determine the effect of the stimulating electrode size on thresholds of RGCs in the degenerate retina, and if stimulation thresholds can be reduced pharmacologically. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Age-related macular degeneration (AMD) is the leading cause of blindness in the industrialized world and it is also the leading cause of blindness among veterans. The veteran population as well as the US population as a whole is aging, and according to the VA's own estimates, the number of veterans with significant visual impairment will reach 430,000 by the year 2011. Research and development of a retinal prosthesis to restore useful vision to blind veterans who have degenerative retinal diseases is a major goal of our Center at the VA Boston Healthcare System. There is no treatment to restore vision to patients who have become blind because of macular disease. The work proposed here has the potential to improve the results of human retinal implants by lowering stimulation thresholds, which would improve the safety margin of a retinal implant, and to increase the quality of visual percepts created by electrical stimulation of the retina.